Dynamic Assembly of the Receptor-G-Protein Signaling Complex

Abstract

The recent crystal structure1 of the β2 adrenergic receptor-Gs protein complex (β2AR-Gs) marks an important milestone in a two decades long race to decipher one of the most important and widely utilized signal-transduction mechanisms in biology. However, it is unclear how the relatively drastic and unexpected conformational changes evolve from the initial encounter complex. The number of compositional and conformational microstates that evolve along the reaction pathway from the initial encounter of agonist-activated receptor with the GDP-bound heterotrimeric G-protein to the nucleotide-free agonist-receptor-G protein ternary complex is potentially very large.2 Identification of these pathways is out of reach for crystallographic experiments, and we follow a complementary approach with large-scale molecular dynamics (MD) simulations of membrane-embedded, fully solvated metarhodopsin II alone and in complex with its cognate G-protein, transducin, in GDP-bound form. Here, we compare and contrast the relaxation of two different encounter complexes, one with an orientation similar to β2AR-Gs, and the other 120° rotated. Interestingly, the two different pre-aligned encounter complexes yield induced-fit complexes that share a signature set of conformational changes involving highly conserved residues in the three allosterically coupled domains, the agonist-binding, G-protein-binding, and nucleotide-binding sites. How are these canonical and non-canonical binding modes possible for such a high fidelity signal-transduction system? Is it possible that Nature utilizes multiple, energetically similar states to relay the information encoded in the relatively small free energy of agonist binding across about ten nanometers distance to the nucleotide-binding pocket? It is tempting to speculate about the role of these energetically near-equivalent microstates when discussing the dominating entropic contribution to the binding free energy of agonists at the β adrenergic receptors.1Rasmussen, et al. (2011) Nature 477, 549.2Huber and Sakmar (2011) Trends. Pharmacol. Sci. 32, 410.